Project Summary/Abstract Pancreatic cancer is the 3rd leading cause of cancer deaths in the United States and its incidence is rising. Three out of four pancreatic cancer patients do not survive a year past diagnosis, and current treatment options extend median survival by only a few months. Moreover, experimental targeted therapies have failed to meaningfully improve patient survival, creating a dire need for new approaches to treating this deadly disease. Select cocktails of chemotherapeutic agents have been shown to improve response rates over their individual components. For example, FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) is now used as a second- line therapy for pancreatic cancer and serves as the foundation for FOLFIRINOX (FOLFOX + irinotecan), a first-line therapy with severely limiting toxicities. FOLFOX has less prohibitive side effects and may be amenable to further drug combination, but there are few studies of signaling responses to FOLFOX and other chemotherapy cocktails. In order to develop novel therapies most likely to be effective in humans, our group performs studies in patient- derived tumor xenograft (PDX) models, which we and others have shown accurately recapitulate patient tumor architecture, genetic heterogeneity, and drug responses. This project will study PDX responses to FOLFOX and additional targeted agents using multiple techniques, including RNA Sequencing and multiplexed kinase inhibitor beads with mass spectrometry (MIB-MS) for quantifying proteomic changes to the global set of protein kinases. We have preliminary data indicating that c-Jun N-terminal kinases (JNK) and upstream mitogen activated protein kinases (MAPKs) are upregulated by FOLFOX, but not by gemcitabine, a similarly acting cytotoxic agent. Therefore, we hypothesize that MAPK-JNK signaling may play a role in directing adaptation and resistance to FOLFOX that can be exploit therapeutically. Aim 1 will determine the mechanism by which FOLFOX induces dynamic upregulation of MAPK-JNK signaling in PDX tumors and evaluate these signaling cascades as promoters of chemoresistance. Aim 2 will target the adaptive kinome by assessing in vivo and in vitro synergy between FOLFOX and pharmacological inhibitors of the potentially synergistic second targets JNK and c-MET. Uncovering specific kinases and signaling molecules involved in the response to chemotherapies may reveal new therapeutic approaches and rational drug combinations. Our studies will provide rationale for therapeutically targeting MAPK-JNK and other FOLFOX-induced signaling responses in pancreatic cancer. Moreover, this experimental and in silico approach will be widely applicable to many cancer types and putative drug combinations. Overall, the superior research and clinical opportunities available to me at the University of North Carolina, my experienced collaborators within our Department of Pharmacology, and the exceptional mentoring of Drs. Jen Jen Yeh and Gary Johnson will all serve to empower me to achieve my experimental goals and advance my development as a physician-scientist.